Scientists have long suspected that genetic and environmental factors work together to cause rheumatoid arthritis (RA). While the exact mechanisms remain a mystery, evidence in support of gene-environment interactions now suggests there may be many pathways to RA. One risk factor strongly implicated in causing RA is smoking. A large body of research persuasively shows the role cigarette smoking can play in RA if the genetic climate is right. Now, scientists are trying to understand how smoking might trigger a particularly aggressive form of RA in certain people.

Gene-environment Interaction in RA

The search for genetic risk factors for RA began in the HLA (human leukocyte antigen) system. HLA molecules play a key role in immune function, and variations in HLA genes have been found in many autoimmune and inflammatory diseases. Sure enough, the first gene linked with RA – the so-called shared epitope (SE) gene – was found in the HLA system. More than 30 genetic risk factors for RA have been revealed since, but the SE gene remains the one most strongly associated with the disease.

But scientists know it takes more than genes to cause RA, as studies in identical twins show. Despite having the same set of genes, an identical twin of someone with RA has roughly a 15 percent risk of also developing RA, indicating that other factors must be at play.

“Even the strongest genetic risk factors are not seen in all people with RA,” explains Ted Mikuls, MD, a rheumatologist and epidemiologist at the University of Nebraska Medical Center in Omaha. “This is true of every risk factor for RA that I am aware of,” he adds. “That tells you just how complex this disease is. There isn’t a single risk factor that explains it.”

Dr. Mikuls is one of a handful of worldwide researchers studying how genetic factors and environmental exposures may influence the risk of RA. Over the past 20 years, several large population-based studies of gene-environment interactions in RA have been conducted in the United States and throughout Europe. Increasingly, these studies show that RA is caused by an interaction of many factors.

Of all environmental factors suspected or described, smoking is by far most convincingly linked with RA. Study after study has implicated smoking as a contributor to the disease in certain people.

“The case for smoking being a risk factor for developing RA is pretty clear cut. This has been a fairly consistent and robust finding,” says Dr. Mikuls. He notes that the evidence is strengthened by the number and quality of the studies linking smoking and RA and by the fact that the studies have been done in varied populations – men and women, Caucasians and African-Americans, and people from many countries.

“But, it’s not just smoking,” adds Dr. Mikuls. “It’s smoking in the context of the right genetic factors – and probably many factors we’ve yet to identify that mediate this risk.”

One factor that often coexists with smoking is the SE gene. Dr. Mikuls describes the smoking/SE gene duo as being “a particularly evil combination in terms of disease risk” because it frequently shows up in people with the more aggressive form of RA that involves formation of antibodies to citrullinated protein antigens (ACPAs). The risk for ACPA-associated RA increases with the total amount of smoking exposure and the number of SE gene copies (zero, one, or two). Smokers with two copies of the SE gene (one from each parent) have 21 times the risk of ACPA-associated RA as nonsmokers with no copies of the SE gene.